Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
Arkadiusz Miążek , Michał Zalas , Joanna Skrzymowska , Bryan A. Bogin , Krzysztof Grzymajło , Tomasz M. Goszczynski , Zachary A. Levine , Jon S. Morrow , Michael C. Stankewich
AbstractThe neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spectrin is cleavage by calpains, a family of calcium-activated proteases. Spectrin cleavage is regulated by activated calpain, but also by the calcium-dependent binding of calmodulin (CaM) to spectrin. The physiologic significance of this balance between calpain activation and substrate-level regulation of spectrin cleavage is unknown. We report a strain of C57BL/6J mice harboring a single αII spectrin point mutation (Sptan1 c.3293G > A:p.R1098Q) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis. Homozygotes are embryonic lethal. Newborn heterozygotes of either gender appear normal, but soon develop a progressive ataxia characterized biochemically by accelerated calpain-mediated spectrin cleavage and morphologically by disruption of axonal and dendritic integrity and global neurodegeneration. Molecular modeling predicts unconstrained exposure of the mutant spectrin's calpain-cleavage site. These results reveal the critical importance of substrate-level regulation of spectrin cleavage for the maintenance of neuronal integrity. Given that excessive activation of calpain proteases is a common feature of neurodegenerative disease and traumatic encephalopathy, we propose that damage to the spectrin MPS may contribute to the neuropathology of many disorders.
|Journal series||Scientific Reports, ISSN 2045-2322, (N/A 140 pkt)|
|Publication size in sheets||0.85|
|License||Journal (articles only); published final; ; with publication|
|Score||= 140.0, 28-04-2021, ArticleFromJournal|
|Publication indicators||= 0; : 2016 = 1.401; : 2019 = 3.998 (2) - 2019=4.576 (5)|
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